From brain to muscle and back : novel approaches to harness the benefits of exercise

As the world population is growing older and more sedentary every day, the need for new approaches to combat chronic diseases grows steadily. Physical exercise improves health and reduces the risk of developing a plethora of chronic diseases. This body of work aims to investigate the molecular mechanisms underlying the neuronal and muscle function, their interaction and the potential signals that mediate this communication.

To gain more insight into neurodegeneration, in paper I, we used a mouse model of Alzheimer’s disease and examined the mechanisms generating amyloid plaques. We discovered that Presenilin 1 (PS1), the key player of the enzyme responsible for generating the pathogenic peptides that make up the plaques, can play a dual role. Upon phosphorylation at a specific site, PS1 can facilitate the degradation of the substrate that would otherwise be cleaved to generate toxic amyloid peptides. This function ultimately reduces soluble amyloid peptide levels as well as the plaque burden. Overall this study extends our understanding of neurodegenerative processes and proposes a new target for intervention.

In paper II, we investigated the transcriptional signatures of inherent and acquired exercise capacity in the skeletal muscle using uniquely developed rodent models. Our results associate high exercise capacity with angiogenesis and oxygenation while low exercise capacity profile reflects gene programs related to inflammation and cardiovascular disease. We interrogated the transcriptome data for potential upstream regulators and also secreted factors that can mediate exercise capacity and response. Finally, we compared the rat transcriptomic signatures with those of humans and identified an overlapping set of genes.

In paper III, we explored the biological function of a muscle-secreted factor called Neurturin (NRTN). Transgenic animals overexpressing NRTN in skeletal muscle are leaner and more glucose tolerant than controls. Their muscles exhibit increased oxidative metabolism and vascularization. We observed a NRTN-induced remodelling in neuromuscular junction morphology and discovered that NRTN can promote a slow motor neuron identity and reduce markers for fast-motor neurons. Functionally, muscle-specific overexpression of NRTN enhances endurance performance and improves motor coordination. Systemic delivery at the adult stage could achieve an improvement in glucose metabolism and also recapitulate the improved motor coordination. We propose NRTN as a myokine with therapeutic promise for metabolic dysfunction and neuromuscular diseases.

List of scientific papers

I. Victor Bustos, Maria Pulina, Yildiz Kelahmetoglu, Fred Gorelick, Marc Flajolet, Paul Greengard. Bidirectional regulation of Aβ levels by Presenilin 1. Proceedings of the National Academy of Sciences. Jul 2017, 114 (27) 7142-7147.
https://doi.org/10.1073/pnas.1705235114

II. Yildiz Kelahmetoglu, Paulo R. Jannig, Igor Cervenka, Lauren G. Koch, Steven L. Britton, Jiajia Zhou, Huating Wang, Matthew M. Robinson, K Sreekumaran Nair, Jorge L. Ruas. Comparative Analysis of Skeletal Muscle Transcriptional Signatures Associated with Aerobic Exercise Capacity or Response to Training in Humans and Rats. Frontiers in Endocrinology. 2020, 11(819).
https://doi.org/10.3389/fendo.2020.591476

III. Jorge C. Correia*, Yildiz Kelahmetoglu*, Paulo R. Jannig, Christoph Schweingruber, Dasa Svaikovskaya, Liu Zhengye, Igor Cervenka, Mariana Oliveira, Jik Nijssen, Vicente Martínez-Redondo, Michael Stec, Naveen Khan, Johanna Lanner, Sandra Kleiner, Eva Hedlund and Jorge L. Ruas. Muscle-secreted neurturin couples fiber oxidative metabolism and slow motor neuron identity. *These authors contributed equally. [Manuscript]